Matrix metalloproteinases (“MMPs”) are a class of zinc-dependent endopeptidase enzymes involved in the degradation and repair of major components of extracellular matrix and connective tissue. MMPs can be found in various cell types that reside in or are associated with connective tissues, such as fibroblasts, monocytes, macrophages, endothelial cells, and also invasive or metastatic tumor cells. MMPs are secreted from cells as latent proenzymes and are activated by Zn-dependent cleavage of the N-terminal part of the protein. When active MMPs are stimulated by growth factors and cytokines in the local tissue environment, they can degrade protein components of extracellular matrix and connective tissue, such as collagen, proteoglycans, fibronectin, and laminin. See H. Birkedal-Hansen, Crit. Rev. Oral. Biol. Med., 1993, 4, 197-250.
Currently, it is known that there are fourteen different MMPs. These enzymes can be classified into several major categories according to their substrate specificities. For example, MMP-1, MMP-8, and MMP-13 are classified as collagenases. MMP-3 and MMP-11 are classified as stromelysins. MMP-2 and MMP-9 are classified as Type IV collagenases/gelatinases.
MMPs are of significant interest because they have been implicated in a wide variety of physiological and pathological conditions. Some examples of conditions known to be mediated by MMPs are tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, restenosis, fibrosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, reproduction, tissue morphogenesis, angiogenesis, skin aging, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection. See M. Cockett, et al., Biochem. Soc. Symp., 1998, 63, 295-313; D. Keiner, et al., Can. Chemo. Pharm., 1999, 43, 42-51; D. Keiner, Cancer Metastasis Rev., 1990, 9, 289-303; J. MacDougall, et al., Mol. Med. Today, 2000, 64, 149-156; J. MacDougall, et al., Cancer Metastasis Rev., 1995, 14, 351-362; S. Curren, et al., Eur. J. Cancer, 2000, 36, 1621-1630.
One particular area of research that has received much attention is the involvement of MMPs with cancer and the growth and spread of tumors. Indeed, the metastatic spread of cancer via proteolytic degradation of host biomatrix poses one of the greatest challenges in the treatment of cancer. Considerable evidence has been accumulated that indicates the involvement of MMPs in general, and of the gelatinases in particular, in local tumor growth, invasion, and metastatic spread of cancer to disseminated sites. For example, the level of expression of MMP-2 and MMP-9 is known to be elevated in certain tumor progression events. These enzymes degrade Type IV collagen, the major component of basement membranes, and denatured collagen (gelatin), leading to tumor metastasis. Also, the disruption of vascular membranes, composed mainly of Type IV collagen, by MMP-2 and MMP-9 is known to play a critical role in tumor metastasis.
Because of the involvement MMPs have in such a wide variety of physiological and pathological conditions, especially cancer and arthritis, synthetic inhibitors of these enzymes are considered attractive targets in drug discovery research. See J. B. Summers, et al., Ann. Rep. Med. Chem., 1998, 33, 131-140; A. H. Davidson, et al., Chem. Ind., 1997, 258-261; J. C. Spurlino, In “Structure-Based Drug Design,” Veerapandian, Ed., Marcel Dekker, Inc., N.Y., 1997, 171-189; R. P. Beckett, et al., Drug Disc. Today, 1996, 1, 16-26. Such research pursuits have resulted in the development of several broad-spectrum peptidyl and partially selective nonpeptidyl MMP inhibitors as potential anticancer and antiarthritis agents. See P. D. Brown, Med. Oncology, 1997, 14, 1-10; P. D. Brown, APMIS, 1999, 107, 174-180; P. D. Brown, Expert Opin. Invest. Drugs, 2000, 9, 2167-2177; J. Freskos, et al., Biorg. Med. Chem. Lett., 1999, 9, 943-948; L. J. MacPherson, et al., J. Med. Chem., 1997, 40, 2525-2532; M. Cheng, et al., J. Med. Chem., 2000, 43, 369-380. However, current results from both preclinical and clinical trials of MMP inhibitors have been disappointing mainly due to poor bioavailability, poor selectivity, and undesirable side effects, such as tissue toxicity and even the promotion of liver metastasis. See “MMPs,” Park W & Mecham R., AP, NY, 1998, pp. 1-14, 85-113, 115-149; M. Michaelides, et al., Curr. Pharma. Design, 1999, 5, 787-819; E. Heath, et al., Drugs, 2000, 59, 1043-1055; L. Seymour, Cancer Treat. Rev., 1999, 25, 301-312; K. Woessner, Ann. NY Aca. Sci., 1999, 878, 388-403; J. Skiles, et al., Ann. Rep. Med. Chem., 2000, 35, 167-176; M. Gowravaram, et al., J. Med. Chem., 1995, 38, 2570-2581; M. Gowravaram, et al., Biorg. Med. Chem. Lett., 1995, 5, 337-342; R. Greenwald, et al., Curr. Opin. Ther. Patents, 1995, 4, 7-16; D. Levy, et al., J. Med. Chem., 1998, 41, 199-223; A. Kruger, et al., Cancer Res., 2001, 61, 1272-1275. Therefore, in light of the clinical complexity associated with current MMP inhibitors, there is currently a need for new, potent inhibitors that more selectively target MMPs.